ClinVar Miner

Submissions for variant NM_000363.4(TNNI3):c.592C>G (p.Leu198Val) (rs727504285)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000518842 SCV000209193 likely pathogenic not provided 2018-12-20 criteria provided, single submitter clinical testing The L198V likely pathogenic variant in the TNNI3 gene has been identified in multiple unrelated individuals with HCM referred for genetic testing at GeneDx and reported in published literature (Maron et al., 2012; Otsuka et al., 2012; Ng et al., 2013; Arad et al., 2014; Coppini et al., 2014; Lopes et al., 2015; Walsh et al., 2017). Moreover, this variant has segregated with disease in affected relatives from several families referred for testing at GeneDx and in the published literature (Otsuka et al., 2012). The L198V variant is not observed in large population cohorts (Lek et al., 2016). Furthermore, missense variants in nearby residues (N194K, D196N, S199N) are independently classified as pathogenic or likely pathogenic by GeneDx. Nonetheless, the L198V variant is a conservative amino acid substitution which is not likely to impact secondary protein structure as these residues share similar properties and in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. In summary, L198V in the TNNI3 gene is interpreted as a likely pathogenic variant.
Invitae RCV000628864 SCV000749772 likely pathogenic Hypertrophic cardiomyopathy 2018-03-22 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 198 of the TNNI3 protein (p.Leu198Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family and in other individuals affected with hypertrophic cardiomyopathy (PMID: 22112859, 27532257, 25524337, 21839045). ClinVar contains an entry for this variant (Variation ID: 177694). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Other missense substitutions at this codon (p.Leu198Arg and p.Leu198Pro) have been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 15698845). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154294 SCV000203953 uncertain significance not specified 2016-08-03 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Leu198Val variant in TNNI3 has been reported in 6 individuals with HCM and segregated with disease in 1 affected relative (Maron 2012, Otsuka 2012, Coppini 2014, Arad 2014, LMM data). However, 2 of these individuals also carried a possible disease-causing variant in MYBPC3. The p.Leu198Val variant was absent from large population studies. Splice prediction tools suggest the creation of a cryptic 5' splice site; however, this information is not predictive enough to determine pathogenicity. Additional computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Leu198Val variant is uncertain.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000623545 SCV000740430 likely pathogenic Primary familial hypertrophic cardiomyopathy 2017-07-12 criteria provided, single submitter clinical testing

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